Summary/abstract: There are no FDA-approved medications for stimulant use disorders. Therapies for opiate use disorders remain suboptimal in ways that are now a focus of national attention. PTPRD (receptor type protein tyrosine phosphatase D) is now supported as a target for development of novel drugs to treat stimulant use disorders by genetic, molecular biologic and pharmacologic evidence in humans and mouse models. Data include: a) multiply-replicated human PTPRD genetic associations (clustered SNPs; 10-8 < p < 10-2) with addiction phenotypes including DSM dependence on opiates and stimulants; b) PTPRD SNP associations with levels of PTPRD expression in postmortem human brain; c) reduced cocaine conditioned place preference (CPP) and cocaine self-administration in mice with 50% reductions in PTPRD expression; d) little human or mouse model evidence for toxicity from reduced PTPRD expression; e) identification of 7-BIA (7-butoxyilludalic acid analog) as a PTPRD ligand that inhibits PTPRD's phosphatase; f) no identified 7-BIA toxicity; g) observations that 7-BIA attenuates both cocaine CPP and well-established cocaine self-administration. Human data supports PTPRD associations with vulnerability to opiate use disorders, though there is presently only preliminary mouse model/pharmacologic support for this association. These exciting results strongly support development of therapeutic PTPRD ligands for stimulant use disorders and studies to seek benefits for opiates. We will thus improve PTPRD ligands, identify effects on opiates and move the best novel, patentable PTPRD ligands toward human studies via i) synthesis of novel PTPRD ligand candidates; ii) testing in vitro activities at PTPRD, related phosphatases and off-target effects. We will seek a) improved potency, b) greater selectivity/few ?off target? effects, c) improved solubility, d) improved stability; e) predicted good half-life; f) predicted bioavailability after oral administration and g) predicted ability to cross the blood brain barrier. Selected compounds will be screened in vivo for toxicities from acute then chronic dosing in mice. Improved compounds will be tested in cocaine conditioned place preference and self-administration assays. In tests of opiate reward, we will examine effects of 7-BIA, improved compounds and heterozygous PTPRD knockout. The best compounds active in CPP/self-administration will be tested for biodistributions/ metabolism/stability, aversive or rewarding effects of their own, motor/memory/sensory effects and mouse/rat toxicity and preIND studies. We will thus generate novel, well tolerated and bioavailable PTPRD ligands that display in vitro potency, selectivity and stability, in vivo modulation of cocaine reward and, likely, modulation of opiate reward at doses that provide no significant toxicity. Grand Opportunity support will provide compounds and data to help underpin IND submission, intellectual property protection, pharmaceutical partnerships and progress from novel lead compound to exciting new anti-addiction drug candidates.